The Model Organism Diaspora
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Heredity (2019) 123:14–17 https://doi.org/10.1038/s41437-019-0191-5 REVIEW ARTICLE The model organism diaspora Jonathan Hodgkin1 Received: 23 November 2018 / Accepted: 20 December 2018 © The Genetics Society 2019 The 1950s and 1960s saw an extraordinary flowering of Phycomyces blakesleeanus, described by him as “the most molecular biology and molecular genetics, which revealed intelligent primitive eukaryote” (cited in Fischer and Lipson many of the fundamental secrets of life. After that era, many 1988). Its sporangiophores exhibit an extraordinary range of of the scientists who had contributed to this Golden Age (no sensory abilities, including a still rather mysterious avoid- exaggeration) of discovery looked around for new worlds to ance behaviour whereby the growing sporangiophore is able conquer and new experimental systems to develop. It was to avoid nearby objects (Cerdá-Olmedo 2001). Delbrück obvious that genetic approaches would provide powerful was originally a physicist, and hoped to discover new kinds tools, especially for investigating complex biological phe- of physics by investigating biology, so the unusual avoid- nomena. Francis Crick once accurately remarked, “Genetics ance phenomenon may have piqued his interest. Research 1234567890();,: 1234567890();,: is great for opening up a problem and fantastic in the on Phycomyces was unfortunately hampered by the diffi- endgame, but in the middle you have to do biochemistry”. culties of its sexual system and by inability to achieve For many, it is the first of these phases that is most transformation with exogenous DNA. Delbrück was also rewarding, but it is still crucial to choose the right system avowedly reluctant to get involved with biochemical details for your preferred problems, not least because of the need to (Strauss 2017). do at least some biochemistry. In contrast, Delbrück’s previous choice of an experi- Consequently, in the space of a decade or so, an intel- mental system, the T bacteriophages of Escherichia coli, lectual diaspora of gifted molecular geneticists took place, had been brilliantly successful. He realized in 1939 that as these scientists chose a variety of different organisms for phage provided an ideal route to understanding the funda- their research. Max Delbrück began to work on Phyco- mental nature and properties of genes, as the subsequent myces, Seymour Benzer and David Hogness on Drosophila, history of the “Phage Group” abundantly demonstrated Sydney Brenner on nematodes, Francois Jacob on mice, (Ellis and Delbrück 1939). However, in the longer run T4, George Streisinger on zebrafish, Gunther Stent on leeches, the most popular of these bacteriophages, proved to have a Cyrus Levinthal on Daphnia, Gerry Fink on Arabidopsis, significant defect as an experimental system. The DNA of Bill Dove on Physarum, Dale Kaiser on myxobacteria, Lee T4 is heavily glucosylated, rendering it resistant to most Hartwell and Ron Davis on yeast, and so on. Some of these restriction enzymes and therefore complicating the appli- organisms, such as Drosophila and Arabidopsis, had been cation of many of the techniques of molecular genetics. This studied for decades by conventional genetic methods, but it difficulty could not have been foreseen. Sometimes, unex- was a more open question as to how amenable they might pected problems are there from the outset, one example be to molecular approaches. being Gregor Mendel’s unlucky decision to test the theories Some of these adventures worked out spectacularly well that he had developed by breeding garden peas, by and some did not, for a variety of reasons. One example of experimenting on a different plant. He chose hawkweed, not an interesting organism that never managed to attract a large knowing that these plants reproduce asexually and are also number of researchers was Delbrück’s choice, the fungus highly heterozygous, so his breeding experiments produced incomprehensible results (Nogler 2006). As well as problems, major unforeseen advantages may also become apparent when a new system is being devel- * Jonathan Hodgkin oped, sometimes from the general investment of experi- [email protected] mental effort and sometimes from sheer good fortune. One 1 Department of Biochemistry, University of Oxford, South Parks spectacular early example was the discovery of polytene Road, Oxford OX1 3QU, UK chromosomes in the salivary glands of Drosophila (Painter The model organism diaspora 15 1933), some 20 years after T. H. Morgan had decided on In subsequent decades, other issues became important, fruit-flies as his preferred genetic system. Polytene chro- notably the ability to clone genes, to transform the organ- mosomes added a huge bonus to research on Drosophila, as ism, and eventually to generate physical maps and complete they provided a means of directly visualizing fine details of sequences of the genome. Genome size was and remains an chromosome structure and thereby permitted far more important factor in experimental tractability, from this point sophisticated cytogenetics than was possible in other of view. Both C. elegans and Arabidopsis thaliana were genetic organisms. Polytene chromosomes continued to be found to have very compact genomes (100 and 135 Mb highly advantageous for decades, especially in the era of respectively), which made them significantly more attrac- molecular gene cloning, with the development of in situ tive for genomic approaches. Towards the other end of the hybridization. scale, the zebrafish Danio rerio has a genome of 1400 Mb, However, Nature’s gift of polytene chromosomes did and obtaining a satisfactory complete genome sequence for have one unhelpful consequence, arising from detailed this organism took many years of effort. mutational analyses of defined intervals in the Drosophila The most popular model organisms all had multiple genome, which led to the beguiling “one chromomere, one advantages and thereby lent themselves to many different cistron” hypothesis (Judd et al. 1972). The possibility that kinds of research. In contrast, some organisms have special each visible polytene chromosome band or chromomere properties that rendered them ideal for certain experimental corresponded to an individual gene was exciting and gen- projects, illustrating the principle enunciated by August erated much theorizing as to the nature of the eukaryotic Krogh (Krogh 1929), and before him by Claude Bernard gene. This was a major issue for many years, partly trig- (Bernard 1865). The protist Tetrahymena, for example, gered by the C value paradox: most eukaryote genomes provided a perfect system for the study of telomeres, contain far more DNA than bacterial genomes, suggesting because the generation of its macronucleus entails frag- that eukaryote and prokaryote genes might be different in mentation of its genome into hundreds of minichromosomes some fundamental way. Sadly, the correspondence between and the creation of correspondingly many telomeres. genes and bands in Drosophila evaporated over time, and Another genetically amenable protist, Paramecium, has both ultimately proved to be no more than accidental. interesting behaviour and cells large enough to permit A much later example of good fortune was the discovery microelectrode penetration and electrophysiological of feeding RNA interference (RNAi) in the nematode experiments, thereby permitting the first genetic analyses of Caenorhabditis elegans (Timmons and Fire 1998). This ion channels. species takes up exogenous double-stranded RNA from the Efficient gene cloning and ease of transformation became environment with much greater efficiency than its close major factors in determining the popularity of research relatives, thereby vastly simplifying the application of organisms. Identification and characterization of transpo- whole-genome RNAi screens. Caenorhabditis elegans had sons, as tools for molecular genetics, also became impor- already proved to be a fortunate choice in other ways, for tant. Antirrhinum majus (snapdragon), for example, is not example, in its optical properties and in the ease with which obviously optimal experimental material, but its Tam it can be frozen and stored indefinitely. transposons enabled the ready isolation of floral homeotic So, some model organisms seem to be blessed, others not mutants and the pioneering elucidation of flower morpho- so much. A variety of strategic factors influenced early genesis by Enrico Coen and collaborators (Carpenter and choices in the 1960s, and it was always clear that no single Coen 1990). organism could satisfy all requirements. These factors The question of what genetic system to choose was one included ease and expense of culture, size, complexity, that came up frequently in my own research experiences in transparency, growth rate, generation time, genetic amen- the 1970s. I was fortunate enough to carry out my doctoral ability, long-term storage, behavioural repertoire, natural research at the MRC Laboratory of Molecular Biology variation, background knowledge, phylogenetic position, (LMB) in Cambridge, working on the nematode worm C. scientific community, and medical or economic relevance. elegans under the supervision of Sydney Brenner, some- Some of these factors significantly influenced funding times known as “Father of the Worm” for his role in pio- decisions. Moreover, there were inevitable trade-offs in neering the use of C. elegans. He attracted and inspired experimental advantages, such as those encapsulated in many talented students and postdoctoral scientists